title: Targeting transmembrane TNF-α suppresses breast cancer growth.
abstract: TNF antagonists may offer therapeutic potential in solid tumors, but patients who have high serum levels of TNF-α fail to respond to infliximab, suggesting consumption of the circulating antibody and loss of transmembrane TNF-α (tmTNF-α) on tumors by ectodomain shedding. Addressing this possibility, we developed a monoclonal antibody (mAb) that binds both full-length tmTNF-α and its N-terminal truncated fragment on the membrane after tmTNF-α processing but does not cross-react with soluble TNF-α. We documented high levels of tmTNF-α expression in primary breast cancers, lower levels in atypical hyperplasia or hyperplasia, but undetectable levels in normal breast tissue, consistent with the notion that tmTNF-α is a potential therapeutic target. Evaluations in vitro and in vivo further supported this assertion. tmTNF-α mAb triggered antibody-dependent cell-mediated cytotoxicity against tmTNF-α-expressing cells but not to tmTNF-α-negative cells. In tumor-bearing mice, tmTNF-α mAb delayed tumor growth, eliciting complete tumor regressions in some mice. Moreover, tmTNF-α mAb inhibited metastasis and expression of CD44v6, a prometastatic molecule. However, the antibody did not activate tmTNF-α-mediated reverse signaling, which facilitates tumor survival and resistance to apoptosis, but instead inhibited NF-κB activation and Bcl-2 expression by decreasing tmTNF-α-positive cells. Overall, our results established that tmTNF-α mAb exerts effective antitumor activities and offers a promising candidate to treat tmTNF-α-positive tumors, particularly in patients that are nonresponders to TNF antagonists.
authors.affiliation: Department of Immunology, Tongji Medical College, Wuhan University, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Yu
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhou
authors.forename: Lin
authors.initials: L
authors.lastname: Niu
authors.forename: Guohong
authors.initials: G
authors.lastname: Lin
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhou
authors.forename: Hui
authors.initials: H
authors.lastname: Gan
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Jiang
authors.forename: Bingjiao
authors.initials: B
authors.lastname: Yin
authors.forename: Zhuoya
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha